The uptake of long chain fatty acids may be be viewed as a special case of a more general aspect of liver function, i.e. the transport of a group of variably amphipathic endogenous compounds, dyes and xenobiotic designated "organic anion." Among these substances, fatty acids are unique in that (a) their net entry into the liver far exceeds that of the others, and (b) they play a central role in the nutrition of the organism as a whole and of the liver in particular. Despite this, control of the hepatic uptake of fatty acids has been characterized to only a limited extent. According to current concepts, uptake: 1) reflects little more than fatty acid concentration in plasma and the fatty acid-albumin molar ratio, 2) is not affected by the properties of the liver cell itself; and 3) is not subject to modulation by factors which influence the distribution of exogenous and endogenous fatty acids between oxidation and esterification pathways, such as nutritional state, insulin and glucagon. However, recent findings in our own and other laboratories indicate that the hepatic uptake of fatty acids is significantly influenced by such diverse factors as nutritional state, sex differences, and certain pharmacologic agents. The findings are not explainable by current concepts. The hepatic uptake process not only directly determines that fraction of overall FFA flux which enters the liver (vs. extrahepatic tissues) but also substantially influences the relative magnitudes of fatty acid oxidation and esterification in the liver cell. Thus, its modulation may constitute a control point of major significance for overall fatty acid metabolism. This proposal outlines a comprehensive multifaceted approach to this important area, with emphasis on kinetic considerations, and the influence of nutritional, hormonal, and pharmacologic factors. Liver perfusion, intact hepatocyte systems, and subcellular fractions will be employed. The possible significance of a lobular gradient of fatty acid uptake and metabolism, and of interaction between plasma FFA and chylomicron remnant triglyceride fatty acids will be examined. These studies will provide new information concerning both the control of hepatic uptake processes, and the regulation of fatty acid metabolism in the liver and in the whole organism.